Whole-exome sequencing identifies recurrent SF3B1 R625 mutation and comutation of NF1 and KIT in mucosal melanoma

Abstract

Mucosal melanomas are a rare subtype of melanoma, arising in mucosal tissues, which have a very poor prognosis due to the lack of effective targeted therapies. This study aimed to better understand the molecular landscape of these cancers and find potential new therapeutic targets. Whole-exome sequencing was performed on mucosal melanomas from 19 patients and 135 sun-exposed cutaneous melanomas, with matched peripheral blood samples when available. Mutational profiles were compared between mucosal subgroups and sun-exposed cutaneous melanomas. Comparisons of molecular profiles identified 161 genes enriched in mucosal melanoma (P<0.05). KIT and NF1 were frequently comutated (32%) in the mucosal subgroup, with a significantly higher incidence than that in cutaneous melanoma (4%). Recurrent SF3B1 R625H/S/C mutations were identified and validated in 7 of 19 (37%) mucosal melanoma patients. Mutations in the spliceosome pathway were found to be enriched in mucosal melanomas when compared with cutaneous melanomas. Alternative splicing in four genes were observed in SF3B1-mutant samples compared with the wild-type samples. This study identified potential new therapeutic targets for mucosal melanoma, including comutation of NF1 and KIT, and recurrent R625 mutations in SF3B1. This is the first report of SF3B1 R625 mutations in vulvovaginal mucosal melanoma, with the largest whole-exome sequencing project of mucosal melanomas to date. The results here also indicated that the mutations in SF3B1 lead to alternative splicing in multiple genes. These findings expand our knowledge of this rare disease.

Whole‐exome sequencing of oral mucosal melanoma reveals mutational profile and therapeutic targets

“…SNV analysis suggested that OMMs contain KIT mutations in approximately 20% of specimens examined. Compared with Hintzsche et al's analysis, the KIT mutation frequency in OMM is similar to that in nasal mucosal melanoma (20%) but lower than that in anorectal and vulvovaginal mucosal melanoma (44-80%) [9]. These results are consistent with prior studies that report that KIT mutations are less common in head and neck mucosal melanoma compared with other sites.…”

“…Thus, our results suggest that OMM displays a mutational signature different from that of cutaneous melanomas. Although other authors have found similar results comparing mucosal melanomas with cutaneous melanomas, these studies were performed without any samples obtained from patients with oral mucosal melanoma specimens [8,9]. Furthermore, our signature analysis showed that in OMM the predominant mutation signature is age-associated signature 1 followed by signature 4.…”

Somatic Mutational Landscape of Splicing Factor Genes and Their Functional Consequences across 33 Cancer Types

“…SF3B1 has been reported to be the most frequently mutated splicing factor gene in hematological malignancies and some solid tumors, such as adenoid cystic carcinoma (Martelotto et al, 2015), breast cancer (Cancer Genome Atlas Network, 2012), pancreatic cancer (Biankin et al, 2012), and melanomas (Martin et al, 2013; Cancer Genome Atlas Network, 2015; Hintzsche et al, 2017). It is a member of the U2 complex and, along with SF3B3 and PHF5A, binds to the branch point nucleotide in the pre-catalytic spliceosome (Yan et al, 2016).…”

An update on head and neck cancer: new entities and their histopathology, molecular background, treatment, and outcome

“…Mutations in KIT are present in 4–39% of MM of various other sites whereas most studies report lower frequencies (approximately 10%) of KIT mutations in MM of the head and neck . A recent study found KIT and NF1 co‐mutated in 20% of MM in the head and neck . Mutations in the TERT promotor region have also been demonstrated in MM of the sinonasal tract .…”